Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug dependence. Environmental stimuli or contexts previously associated with drug use can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Reinstatement of responding for drug-associated conditioned cues, both discrete and contextual, following chronic drug self-administration has been demonstrated in rats. Although the role of conditioned cues is well recognized as a factor in relapse, only recently has the fundamental neural circuitry of relapse to various drugs of abuse been explored in detail. Using an extinction/reinstatement model of relapse, the role of the basolateral amygdala complex has been shown to be critical in the acquisition, consolidation, and expression of drug-cue associations that drive relapse. Furthermore, the circuitry of conditioned-cued reinstatement engages a network of brain nuclei that include discrete subregions of the prefrontal cortex and nucleus accumbens. Although extinction/reinstatement paradigms allow investigators to isolate specific features of stimuli that elicit relapse, human addicts generally do not undergo explicit extinction training upon cessation of drug use. Recent studies from our laboratory suggest that activation of the neural circuitry underlying relapse to drug-seeking after abstinence from the drug and the drug-paired environment is uniquely different from that engaged following explicit extinction training. These findings have implicated a significant role of the dorsolateral caudate-putamen (dlCPu) in mediating relapse following abstinence. In this competing renewal application, studies are proposed to test the global hypothesis that neuroadaptive changes in the dlCPu underlie habitual drug-seeking following abstinence from chronic cocaine self-administration. Specifically, we hypothesize that the dlCPu is a key regulator of habit learning that drives compulsive drug-seeking during relapse after abstinence. These changes are hypothesized to involve a change in neuronal activity of the dlCPu as manifested by changes in specific dopamine and glutamate receptor-mediated cell signaling cascades and increased dopamine and glutamate release in the dlCPu during relapse. These experiments provide an integrated approach employing behavioral, molecular biological, and neurochemical techniques aimed at understanding the neuronal bases of long-term conditioned associations produced during and after chronic cocaine self-administration. Information gained from this project will provide direction for development of anti-relapse medications for the treatment of cocaine dependence, as well as other drugs of abuse.